JP2007190112A - Microneedle - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide the shape of a microneedle suitable for the percutaneous administration of a medicament, hardly broken or bent. <P>SOLUTION: The microneedle is made of a resin. The ratio H1/D1 of the height H1 to the diameter of the bottom D1 of the body 12 of the microneedle is at least 1.5 and not more than 3.0, and the ratio H2/D2 of the height H2 of the apex 11 to the diameter of the bottom D2 is at least 0.5 and less than 1.5. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to a microneedle for transdermal administration of a drug.

  In general, drugs that cannot be administered orally are administered by injection. Administration with a syringe causes severe skin damage and is painful. On the other hand, transdermal administration such as a patch is convenient, and further, it is possible to control the drug delivery for locally delivering the drug. It is also said that side effects of drugs can be reduced or avoided. However, when transdermal patches are used, it takes time to develop the drug effect, and the types of drugs that can be administered are greatly limited.

  Such a technique has been developed that overcomes the obstacle that it takes time to develop the drug effect and the types of drugs to be administered are limited.

  Iontophoresis is a method in which a voltage is applied to the periphery of the skin to be administered, and the charged drug is actively percutaneously absorbed by an electrochemical potential. Sonophoresis is a technique for enhancing the transdermal absorbability of a drug by applying ultrasonic waves to the skin through a medium such as an aqueous solution. Electroporation is a method of introducing a drug by applying a high voltage to a cell membrane to reversibly form small pores. In iontophoresis, the current value can be increased to increase the efficiency of drug absorption, but irritation to the skin is a concern. Since sonophoresis and electroporation directly reduce the barrier action of the skin, there are concerns about damage to the skin and associated damage, restoration of the barrier function against infection, and the like. The drugs that can be indicated by any method are limited. That is, iontophoresis requires the drug to be charged in an aqueous solution, sonophoresis and electroporation have low reactivity with the skin, and the molecular weight of the drug must be small.

  In the transdermal administration of drugs, it is known that the obstacle to drug delivery is the stratum corneum in the surface layer of the skin. In recent years, in order to overcome the obstacles, development of microneedles and microblades that deliver drugs while avoiding the stratum corneum has been actively performed (see Patent Documents 1 and 2).

  A microneedle is generally a microneedle having a length of several hundreds μm and a diameter of several tens of μm, and has a large aspect ratio (see Patent Document 3).

  Microneedles are known not only for drug delivery but also for use as a device for body fluid sampling (see Patent Document 4).

  The microneedle has a length enough to penetrate the stratum corneum in the upper layer of the skin but does not reach the pain point. Therefore, there is an advantage that it is not necessary to feel pain associated with skin penetration during application. Since the diameter of the microneedle is as small as several tens of μm, the damage to the skin is much smaller than when an injection needle or a microblade is applied.

  Several reports have been made that microneedles can be an alternative to injection (see Non-Patent Document 1).

  Conventional microneedles have been proposed by a method using optical lithography (see Patent Document 5) or a method using deep reactive ion etching (see Patent Document 6).

  Many of the materials used for the microneedles are metal or silicon (see Non-Patent Document 1). Since the metal or silicon microneedles are excellent in rigidity, it is easy to ensure the rigidity necessary for penetrating the stratum corneum even with a microneedle having a thickness of several tens of microns. However, the microneedle has a problem in toughness. When the microneedle is applied, there is a risk that a part of the tip of the microneedle is broken in the living body or the microneedle is broken from the base, so that metal or silicon is placed in the body.

  A microneedle using a resin such as polyamide or polyester has also been proposed (see Patent Document 7). There is a possibility that microneedles produced using a resin are safer than metal or silicon microneedles. This is because resin is superior in toughness compared to metal, and resin-made microneedles have the property of being difficult to break.

  Microneedles are dosing devices that are characterized by painlessness when applied and little damage to the skin. In addition, resin-made microneedles have the advantage of being hard to break because they are superior in toughness compared to metal.

  However, since the rigidity of the resin is smaller than that of metal or silicon, the conventional resin microneedles tend to be bent and not pierce the skin.

  In order to solve this problem, it is not appropriate to compensate for the low rigidity of the resin by thickening the microneedles. This is because the thicker the microneedles, the less likely it is to penetrate the skin. In addition, when the microneedle is thick and long, and is enlarged in a similar shape, there is a possibility that the advantage of the microneedle that it is painless at the time of adaptation and the damage to the skin is small may be lost.

  The shape of the microneedle needs to be thick enough not to bend and thin so that it can be easily pierced. That is, the shape of the microneedle needs to satisfy these two conditions at the same time, and it is difficult to realize such a shape.

Accordingly, the conventional microneedle shape cannot be bent and easily pierced.
Special Table 2002-517300 Special table 2000-512529 Special table 2005-533625 public information JP 2005-246595 A Japanese translation of PCT publication No. 2004-526581 Special table 2004-538106 gazette Japanese translation of PCT publication No. 2003-501161 D. V. McAllister et al., “Microfabricated needles for transnational deliberation of macromolecules and nanoparticulates: Fabrication methods and transport studies, Proceedings of transport and studies.” 100, no. 24, p. 13755-13760

  It is an object of the present invention to provide a microneedle that is suitable for transdermal administration of a drug and is difficult to bend and bend easily.

  In order to solve the above problems, the present invention has the following configuration.

  The present invention is a resin microneedle, and when the microneedle is divided into a top part and a body part, the ratio H1 / D1 of the body part height H1 to the bottom surface diameter D1 is 1.5 or more and 3.0 or less. Yes, H2 / D2 of the top height H2 and the bottom diameter D2 is 0.5 or more and less than 1.5.

  According to the present invention, it is possible to obtain a resin microneedle that perforates the skin without bending when a drug is transdermally administered.

  The inventors of the present invention have intensively studied microneedles that are difficult to bend and that can perforate the skin, and have solved the above problems by molding the microneedles into a specific shape, and have achieved the present invention.

  The microneedle of the present invention is a resin-made microneedle, and the ratio H1 / D1 between the height H1 of the body portion of the microneedle and the bottom surface diameter D1 is 1.5 or more and 3.0 or less, and the height of the top portion. A microneedle having a ratio H2 / D2 between H2 and a bottom surface diameter D2 of 0.5 or more and less than 1.5.

The microneedle of the present invention is illustrated in FIG.
In the microneedle of the present invention, the top part and the body part are defined as follows.
When the microneedle is composed of two types of structures having different taper angles as shown in FIGS. 2A to 2D, the top is the structure above the microneedle, and the body is the microneedle. It is a lower structure.
As shown in FIG. 2E, when the microneedle is composed of three or more types of structures, or as shown in FIG. When it cannot be specified, a portion having an outer diameter of 70% of the outer diameter D1 of the bottom portion is defined as a boundary surface between the trunk portion and the top portion. When there are a plurality of portions having an outer diameter of 70% of the outer diameter D1 of the bottom, the lowermost surface is defined as a boundary surface between the trunk and the top.
In addition, as shown in FIG. 2 (g), when the microneedle is composed only of a structure having a constant taper angle, such as a truncated cone or a quadrangular prism, the microneedle is composed only of the body portion, and the top portion is The aspect ratio of the top at that time is 0.

  Furthermore, the microneedle of this invention is demonstrated using FIG.

  The aspect ratio of the trunk is the ratio H1 / D1 of the bottom diameter D1 of the trunk and the height H1, and the aspect ratio of the top is the ratio H2 / D2 of the bottom diameter D2 of the top and the height H2. However, when the shape of the bottom is not a circle but a polygon, the diameters D1 and D2 are the diameters of the circumscribed circle of the polygon.

Usually, since the microneedle is integrally formed on the sheet, the boundary between the sheet and the microneedle is not clear, and it is often difficult to determine the bottom diameter D1 of the body portion of the microneedle under a unique condition. The bottom surface diameter D1 of the trunk portion in the present invention is obtained from the intersection of the expanded surface and the sheet by expanding the side surface of the portion of the microneedle having a height of 10 μm to 20 μm while maintaining the taper angle toward the bottom. Magnitude. However, when the taper angle of the portion of the microneedle having a height of 10 μm or more and 20 μm or less is not constant, the side surface is expanded so as to maintain the taper angle of the portion of the microneedle having a height of 15 μm.
The aspect ratio H1 / D1 of the trunk is 1.5 or more and 3.0 or less, preferably 1.7 or more and 2.5 or less.

  The trunk portion is a columnar portion that plays a role of supporting a load during skin perforation, is sufficiently thick to give the strength not to bend, and is preferably long to facilitate skin perforation. By setting the aspect ratio H1 / D1 of the trunk to 1.5 or more and 3.0 or less, it is possible to design a microneedle having a length necessary for skin perforation and having rigidity sufficient not to bend during skin perforation. . If the aspect ratio H1 / D1 of the trunk is less than 1.5, the microneedles may become thicker and shorter, and the skin may not be pierced. Moreover, when the aspect ratio H1 / D1 of the trunk portion exceeds 3.0, it is difficult to ensure rigidity sufficient not to bend when the skin is pierced.

  The top aspect ratio H2 / D2 is 0.5 or more and less than 1.5, preferably 0.7 or more and 1.2 or less.

  The top portion is a tip portion of a microneedle having a role of cutting and piercing the skin at the time of skin perforation. By setting the aspect ratio H2 / D2 of the top to 0.5 or more and less than 1.5, it is possible to maintain sufficient rigidity for skin perforation. When the aspect ratio H2 / D2 of the top is less than 0.5, it is difficult to make the top a sharp shape for perforating the skin. Further, when the aspect ratio H2 / D2 of the top is 1.5 or more, it is difficult to ensure rigidity sufficient not to bend when the skin is perforated.

  The ratio H1 / D1 between the height H1 of the body portion of the microneedle and the bottom surface diameter D1 is 1.5 or more and 3.0 or less, and the ratio H2 / D2 between the height H2 of the top portion and the bottom surface diameter D2 is 0.5 or more and 1 The shape of a macroneedle that is less than .5 is a combination of a cylinder and a truncated cone (FIG. 2A), a combination of a prism and a truncated pyramid (FIG. 2B), and a combination of a truncated cone and a truncated cone-like structure. (FIG. 2 (c)), a combination of two truncated pyramids (FIG. 2 (d)), etc., but limited to these as long as it is a combination of columnar structures such as a cylinder, a truncated cone, a prism, and a truncated pyramid. Not. Further, the boundary between the body part and the top part does not need to be clear, and the taper angle may continuously change as shown in FIG.

  The ratio D2 / D1 of the bottom diameter D2 of the top of the microneedle of the present invention to the bottom diameter D1 of the trunk is preferably 0.5 or more and 1.0 or less, more preferably 0.6 or more and 1. 0 or less. When the diameter ratio D2 / D1 is less than 0.5, the taper angle 14 becomes small, the rigidity at the top of the torso is lowered, or only the bottom of the torso is thick. It is not preferable because it may be difficult to insert the above. If the ratio of diameters D2 / D1 exceeds 1.0, the taper angle 14 exceeds 90 °, and the rigidity at the bottom of the body may be lowered, which is not preferable. By setting the diameter ratio D2 / D1 within the range of 0.5 to 1.0, it is possible to limit the taper angle of the body portion within an appropriate range and ensure the rigidity required when skin is perforated. is there.

  The ratio D3 / D2 of the top diameter D3 of the top of the microneedle of the present invention to the bottom diameter D2 of the top is preferably 0.1 or more and 0.6 or less, more preferably 0.1 or more and 0.4. It is as follows. A diameter ratio D3 / D2 of less than 0.1 is not preferable because the taper angle 15 is increased and a large load may be required to cut the skin. Further, if the diameter ratio D3 / D2 exceeds 0.6, the rigidity of the tip of the top may be remarkably lowered, which is not preferable. By setting the diameter ratio D3 / D2 within the range of 0.1 to 0.6, it is possible to limit the taper angle 15 of the apex to an appropriate range and easily cut the skin at the time of skin perforation. . However, when the shape of the top surface of the top is not a circle but a polygon, the diameter D3 is the diameter of the circumscribed circle of the polygon.

  In the microneedle of the present invention, the ratio H1 / H of the body height H1 and the microneedle height H is preferably 0.5 or more and 0.95 or less, more preferably 0. 0.7 or more and 0.95 or less. Since the trunk portion plays a role of supporting a load during skin perforation, it is preferable that the trunk portion occupies most of the microneedles compared to the top portion. If the ratio H1 / H between the body height H1 and the microneedle height H is less than 0.5, the top will constitute the majority of the microneedle, and the top may be deformed during skin perforation. This is not preferable. Further, when the ratio H1 / H between the height H1 of the trunk portion and the height H of the microneedle exceeds 0.95, the shape of the top portion is limited, and it becomes difficult to obtain a sharp shape for cutting the skin. For this reason, it is not preferable. The ratio H1 / H between the height H1 of the body portion and the height H of the microneedle is 0.5 or more and 0.95 or less, so that the body portion is included in a more rigid ratio with respect to the microneedle, and The shape of the top portion can also take a more preferable shape for perforating the skin.

  In the microneedle of the present invention, the bottom surface diameter D1 of the body part is preferably 30 μm or more and 100 μm or less, more preferably 40 μm or more and 80 μm or less. When the bottom surface diameter D1 of the trunk portion is less than 30 μm, it is difficult to ensure the rigidity of the microneedle for piercing the skin, which is not preferable. When the bottom diameter D1 of the trunk exceeds 100 μm, it is not preferable because the microneedle is too thick and it is difficult to perforate the skin, or damage to the skin may be increased more than necessary.

  The microneedle of the present invention preferably has a height H of 100 μm or more and 300 μm or less. The height H is more preferably 150 μm or more and 250 μm or less. When the height H of the microneedle is less than this range, the skin is flexible, and therefore, the microneedle may not be able to puncture the skin simply by pushing the skin at the time of puncturing the skin. In addition, if the height H exceeds 300 μm, it may be difficult to ensure the rigidity necessary for the microneedles to perforate the skin, or the skin may be damaged more than necessary. I don't like it.

  In the microneedle of the present invention, the top surface diameter D3 is preferably 1 μm or more and 30 μm or less. The top surface diameter D3 of the top is more preferably 1 μm or more and 20 μm or less. When the top surface diameter D3 exceeds 30 μm, the load necessary for skin perforation increases, and the microneedles are easily bent during skin perforation, which is not preferable.

  In the microneedle of the present invention, the shape of the body portion is preferably a truncated cone shape or a polygonal truncated cone shape.

  In the microneedle of the present invention, the shape of the top portion is preferably a truncated cone shape or a polygonal truncated cone shape.

  The microneedle of the present invention is a resin microneedle. The microneedle of the present invention is preferably molded from a resin mainly composed of a thermoplastic resin. The microneedle of the present invention is more preferably made of a resin mainly composed of a polyester resin. Most preferably, the resin disclosed in Japanese Patent Application No. 2005-323033 can be used for the microneedle of the present invention. By molding microneedles using such a resin, it is possible to produce microneedles that can perforate the skin and do not bend easily.

  One microneedle of the present invention may be used, or a plurality of microneedles may be arranged so that the plurality of microneedles can perforate the skin at a time. However, if the microneedles are arranged too densely, the microneedles will not push the skin as a point but a face, making it difficult to perforate the skin. When arranging a plurality of microneedles, it is preferable that the interval between the microneedles be equal to or greater than the height of the microneedles.

  The microneedle and microneedle assembly of the present invention can be used as a perforation device for sampling biological fluids such as blood.

  In order to perform the sampling, the microneedle is pressed for 1 to 5 minutes on the site where the body fluid to be sampled is placed to perforate the skin, and the body fluid discharged from the perforated site may be collected. From the viewpoint of microneedle rigidity and skin elasticity, the pressing force is preferably such that a force within a range of 1.0 gf or more and 15.0 gf or less is applied to each microneedle. A force within the range of 10.0 gf or less is more preferable. Below this range, the skin may not be sufficiently perforated. If it exceeds 15.0 gf per microneedle, the microneedle may be deformed during perforation, and the skin may be damaged when the microneedle is pulled out from the skin.

  When the microneedle of the present invention is used, it is possible to introduce a drug into the body. The drug can be introduced by attaching the drug to the microneedles and then pressing the microneedle against the skin to penetrate the upper stratum corneum of the skin. Alternatively, after the skin is pierced by a microneedle to which no drug is attached, the macroneedle is removed from the skin, and the drug can be introduced into the hole formed by the piercing. From the viewpoint of microneedle rigidity and skin elasticity, the force for pressing the microneedles is preferably such that a force within the range of 1.0 gf to 15.0 gf is applied to each microneedle, A force within the range of 2.0 gf to 10.0 gf is more preferable. Below this range, the skin may not be sufficiently perforated and the drug may not penetrate subcutaneously. If it exceeds 15.0 gf per microneedle, the microneedle may be deformed during perforation, and the skin may be damaged when the microneedle is pulled out from the skin.

  Examples of drugs that can be used include antibiotics, antiviral agents, anti-inflammatory agents, antitumor agents, analgesics, anesthetics, antidepressants, anti-arthritic agents, appetite suppressants, proteins, peptides, vaccines (DNA vaccines And adjuvant), but is not limited to these and can be used.

  In addition, as a method of attaching the drug to the microneedle of the present invention, a method of attaching the drug after forming the microneedle of the present invention, or mixing, coating and coating in a resin for forming the microneedle of the present invention Examples of the method include forming a microneedle after impregnation (swelling), and any method may be used, and the method is not limited thereto, and a method that allows a drug to adhere to the microneedle is arbitrarily used. be able to.

  As an example of the method of attaching the drug after forming the microneedle of the present invention, a method of applying the drug to the microneedle of the present invention, forming a coating film of the drug on the surface and / or swelling the drug in the microneedle (Coating method), a method in which the tip of the microneedle of the present invention is immersed in the liquid surface of the drug, a coating film of the drug is formed on the tip surface of the microneedle, and / or a drug is swollen in the tip of the microneedle (stamp method), etc. However, it is not limited to these.

  The microneedle of the present invention can be used as an acupuncture needle in acupuncture treatment. In the treatment, it is preferable that the force for pressing the microneedle is applied within the range of 1.0 gf to 15.0 gf per microneedle from the viewpoint of the rigidity of the microneedle and the elasticity of the skin. Yes, a force within a range of 2.0 to 10.0 gf is more preferable. Below this range, the skin may not be sufficiently perforated. If it exceeds 15.0 gf per microneedle, the microneedle may be deformed during perforation, and the skin may be damaged when the microneedle is pulled out from the skin.

  Examples of the method for producing the microneedle of the present invention include, but are not limited to, press molding, injection molding, lithography, and etching. More preferably, the imprint molding disclosed in Japanese Patent Application No. 2005-323033 can be used. By using the disclosed processing method by imprint molding, the microneedle can be formed on the resin film with high transfer accuracy.

  Hereinafter, the present invention will be specifically described with reference to examples. However, the present invention is not limited to the following examples.

(Characteristic evaluation method)
A. Buckling test The microneedle was pushed in from above, and the load when the microneedle was bent was measured. The measuring device was a micro compression tester MCTE-500 manufactured by Shimadzu Corporation, and the indenter was a flat indenter made of diamond (diameter 50 μm). The load speed was constant (7.747 mN / sec) and the microneedle was pushed. The buckling load is a linear approximation of the data obtained in the region of displacement = 0 mm to about 2 mm and displacement = about 5 mm to about 8 mm in the load-displacement diagram obtained by the buckling test. Calculated (see FIG. 5).

B. Shape Observation The surface of the mold and the molded product was photographed at 1000 times using a scanning electron microscope S-4800 (model name) manufactured by Hitachi High-Technologies Corporation. For the molded product, platinum was vapor-deposited before observation.

C. Skin perforation test The test was performed in the following procedure. The skin of the back of an 8-week-old hairless mouse was removed and fixed in a stretched state without wrinkles on the stage. Next, the microneedle produced on the sheet was placed on the skin so that the microneedle was on the skin side, and a weight of 500 g was gently placed thereon. After standing in that state for one minute, the weight was removed, the microneedle assembly was removed from the skin, and the entire surface of the skin was stained with Evans Blue 2% aqueous solution (Sigma Aldrich Co., Ltd.). Next, in order to remove the stained cells on the skin surface, an operation (tape stripping) of attaching and peeling an adhesive tape on the skin surface was performed twice. After removing the dyed portion of the entire surface by tape stripping, the number of spots stained blue in dots was counted, and the number of perforated holes was obtained. The ratio (%) of the number of microneedles that could perforate the skin was obtained by the following formula.
Perforation probability (%) = (number of perforated portions / number of microneedles molded on a sheet) × 100
In addition, the shape of the microneedle after the perforation test is observed with a scanning electron microscope, the number of microneedles bent by the perforation is counted, and the ratio of the number of deformed microneedles (deformation probability) (%) is expressed by the following formula: I asked for.
Deformation probability (%) = (number of bent microneedles / number of microneedles molded on a sheet) × 100
The condition that the microneedle is deformed is that the angle formed by the straight line connecting the tip to the bottom of the microneedle and the vertical direction of the sheet is 30 ° or more.

(Reference example)
The microneedle was produced as follows.

  Microneedles were formed on a resin film by imprint molding. The casting mold used for imprint molding was produced as follows. First, a master serving as a template was prepared by selectively irradiating the surface of polymethyl methacrylate (PMMA) with synchrotron radiation, decomposing the irradiated portion, and developing the master. Synchrotron radiation having a wavelength of 0.6 nm or less was used as the exposure light source. For the microneedle mold having a height of 100 μm, the exposure time was 60 minutes and the exposure amount was 15.4 amperes · minute. For the microneedle mold having a height of 150 μm, the exposure time was 90 minutes and the exposure amount was 23.0 ampere · minute. During exposure, the mask was rotated in a plane perpendicular to the traveling direction of the radiated light to continuously change the exposure amount on the side surface of the microneedle, thereby providing a taper. Beryllium was used for the mask membrane and gold was used for the masking material. In order to develop PMMA after exposure, as a developer, 60% by volume of 2-(-butoxyethoxy) ethanol, 20% by volume of tetrahydro-1,4-oxazine, 5% by volume of aminoethanol, and pure water are used. What mixed 15 volume% was used. The development time was 2 hours.

  The produced master was electroformed with nickel and then PMMA was dissolved in a solvent to obtain a mold.

  Next, a fluororesin coat was applied to the mold. The coating agent used was Optool DSX (Daikin Chemical Industries, Ltd., 20% solid solution) diluted to 0.2% solids with a fluorine-based solvent (Daikin Chemical Industries, Ltd., demnum solvent).

  The resin film used for producing the microneedle was produced as follows. Cyclohexanedimethanol 25 mol% copolymerized polyethylene terephthalate dried at 140 ° C. for 2 hours was heated and melted at 280 ° C. in an extruder, extruded from a die onto a cast drum at 25 ° C., and cooled to obtain a 200 μm thick film ( Sample A).

  Production of microneedles by imprint molding was performed as follows. On a lower plate of a press machine having a heating / cooling function, it was placed on a mold stage so that the concavo-convex surface was on top, and a film (sample A) cut into a 3 cm square was placed on it. Next, the upper and lower plates were heated to 140 ° C., and after the temperature reached 140 ° C., the plates were held for 5 minutes. Next, while maintaining 140 ° C., the upper plate was lowered, and the mold and the film were pressed by the upper and lower plates at a pressure of 5.5 MPa. After 4 minutes, the upper and lower plates were cooled to 60 ° C. over 10 minutes while maintaining the press pressure. After cooling to 60 ° C., the press was released, the mold was lowered from the stage without peeling off the film, and air-cooled for 20 minutes. After cooling, the film was released from the mold to obtain microneedles formed on the sheet.

Example 1
According to the reference example, 12 sheets of 100 microneedles as shown in FIG. 4 formed on the sheet were prepared (samples 100 to 111). The layout of the microneedles on the sheet was as shown in FIG.

  One of the produced sheets (sample 100) was observed with a scanning electron microscope, and it was confirmed that the formed microneedle was molded into a shape as shown in FIG. 4 (FIG. 5). The formed microneedle had a body bottom diameter D1 of 36 μm and a height H1 of 91 μm, a top bottom diameter D2 of 20 μm, a top diameter D3 of 10 μm, and a height H2 of 11 μm (Table 1).

  Of 100 microneedles formed on one of the produced sheets (sample 101), 10 were randomly selected to perform a buckling test. One of the load-displacement diagrams obtained by the buckling test is shown in FIG. The average buckling load of the 10 microneedles was 1.88 gf. When the microneedle after the test was observed with an optical microscope, it was found that the microneedle was submerged in the substrate while maintaining its shape without bending.

  A skin perforation test was performed on 10 sheets of the prepared sheets (samples 102 to 111) (Table 2). According to 10 skin puncture tests, the average puncture probability was 92.0%.

  Moreover, the deformation | transformation probability of the microneedle (samples 102-111) after a piercing | boring test was calculated | required (Table 2). According to 10 skin perforation tests, the average deformation probability was 0.4%. As a result of observation, no microneedle damaged by perforation was found.

  From the above, it was revealed that the microneedle shown in FIG. 4 has sufficient rigidity for skin perforation.

(Example 2)
According to the reference example, 12 sheets of 100 microneedles as shown in FIG. 7 formed on the sheet were prepared (samples 200 to 211). The layout of the microneedles on the sheet was as shown in FIG.

One of the produced sheets (sample 200) was observed with a scanning electron microscope, and it was confirmed that the formed microneedle was molded into a shape as shown in FIG. The formed microneedle had a barrel bottom diameter D1 of 52 μm and a height H1 of 120 μm, a top bottom diameter D2 of 30 μm, a top diameter D3 of 10 μm, and a height H2 of 30 μm (Table 1).
Of 100 microneedles formed on one of the produced sheets (sample 201), 10 were randomly selected to perform a buckling test. The average buckling load of the 10 microneedles was 1.83 gf. When the microneedle after the test was observed with an optical microscope, it was found that the microneedle was submerged in the substrate while maintaining its shape without bending.

  A skin perforation test was performed on 10 sheets (samples 202 to 211) of the produced sheets (Table 2). According to 10 skin puncture tests, the average puncture probability was 95.8%.

  Moreover, the deformation | transformation probability of the microneedle (samples 202-211) after a piercing | boring test was calculated | required (Table 2). According to 10 skin perforation tests, the average deformation probability was 0.5%. As a result of observation, no microneedle damaged by perforation was found. From the above, it became clear that the microneedle shown in FIG. 7 has sufficient rigidity for skin perforation.

(Example 3)
According to the reference example, 12 sheets each having 100 microneedles as shown in FIG. 8 formed on the sheet were prepared (samples 300 to 311). The layout of the microneedles on the sheet was as shown in FIG.

  One of the produced sheets (sample 300) was observed with a scanning electron microscope, and it was confirmed that the formed microneedle was molded into a shape as shown in FIG. The formed microneedle had a bottom surface diameter D1 of 40 μm and a height H1 of 70 μm, a bottom surface diameter D2 of 28 μm, a top surface diameter D3 of 10 μm, and a height H2 of 30 μm (Table 1). Of 100 microneedles formed on one of the produced sheets (sample 301), 10 were randomly selected to perform a buckling test. The average buckling load of the 10 microneedles was 1.95 gf. When the microneedle after the test was observed with an optical microscope, it was found that the microneedle was submerged in the substrate while maintaining its shape without bending.

  A skin perforation test was performed on 10 sheets (samples 302 to 311) of the prepared sheets (Table 2). Based on 10 skin perforation tests, the average perforation probability was 92.6%.

  Moreover, the deformation | transformation probability of the microneedle (samples 302-311) after a piercing | boring test was calculated | required (Table 2). According to 10 skin perforation tests, the average deformation probability was 0.4%. As a result of observation, no microneedle damaged by perforation was found. From the above, it was revealed that the microneedle shown in FIG. 8 has sufficient rigidity for skin perforation.

(Comparative Example 1)
According to the reference example, 12 sheets of 100 microneedles as shown in FIG. 9 formed on the sheet were prepared (samples 400 to 411). The layout of the microneedles on the sheet was as shown in FIG.

  One of the produced sheets (sample 400) was observed with a scanning electron microscope, and it was confirmed that the formed microneedle was molded into a shape as shown in FIG. 9 (FIG. 10). The formed microneedle had a bottom surface diameter D1 of 55 μm and a height H1 of 12 μm, a bottom surface diameter D2 of 38.5 μm, a top surface diameter D3 of 9 μm, and a height H2 of 88 μm (Table 1). .

  Of 100 microneedles formed on one of the produced sheets (sample 401), 10 were randomly selected to perform a buckling test. The average buckling load of the 10 microneedles was 0.81 gf. When the microneedle after the test was observed with an optical microscope, it was found that the microneedle was bent at a position of about 50 μm in height.

  A skin perforation test was performed on 10 sheets (samples 402 to 411) of the produced sheets (Table 2). According to 10 skin piercing tests, the average piercing probability was 71.2%.

  Moreover, the deformation | transformation probability of the microneedle (samples 402-411) after a piercing | boring test was calculated | required (Table 2). According to ten skin perforation tests, the average deformation probability was 13.1%. As a result of observation, no microneedle damaged by perforation was found. From the above, it has been found that the microneedle shown in FIG. 9 may not be sufficiently rigid for skin perforation.

(Comparative Example 2)
According to the reference example, 12 sheets of 100 microneedles as shown in FIG. 11 formed on the sheet were prepared (samples 500 to 500). The layout of the microneedles on the sheet was as shown in FIG.

  One of the produced sheets (sample 500) was observed with a scanning electron microscope, and it was confirmed that the formed microneedle was molded into a shape as shown in FIG. 11 (FIG. 12). The formed microneedles had a bottom surface diameter D1 of 38 μm, a top surface diameter D2 of 10 μm, and a height H1 of 100 μm (Table 1). Since the formed microneedle has a constant taper angle, the top surface diameter D3 and the height H2 of the top were set to 0 μm.

  Of 100 microneedles formed on one of the produced sheets (sample 501), 10 were randomly selected to perform a buckling test. The average buckling load of the 10 microneedles was 1.08 gf. When the microneedle after the test was observed with an optical microscope, it was found that the microneedle was bent so as to fall from near the root.

  A skin perforation test was performed on 10 sheets (samples 502 to 511) of the prepared sheets (Table 2). According to 10 skin piercing tests, the average piercing probability was 83.6%.

  Moreover, the deformation | transformation probability of the microneedle (sample 502-511) after a piercing | boring test was calculated | required (Table 2). According to 10 skin perforation tests, the average deformation probability was 3.8%. As a result of observation, no microneedle damaged by perforation was found. From the above, it was found that there is a possibility that the microneedle shown in FIG. 11 cannot be said to have sufficient rigidity for skin perforation.

(Comparative Example 3)
In accordance with the reference example, 12 sheets of 100 microneedles as shown in FIG. 13 formed on the sheet were prepared (samples 600 to 611). The layout of the microneedles on the sheet was as shown in FIG.

  One of the produced sheets (sample 600) was observed with a scanning electron microscope, and it was confirmed that the formed microneedle was formed into a shape as shown in FIG. 13 (FIG. 14). The formed microneedle had a bottom surface diameter D1 of 36 μm and a height H1 of 141 μm, a bottom surface diameter D2 of the top of 15 μm, a top surface diameter D3 of 9 μm, and a height H2 of 9 μm (Table 1). Of 100 microneedles formed on one of the produced sheets (sample 601), 10 were randomly selected to perform a buckling test. The average buckling load of the 10 microneedles was 1.55 gf. When the microneedle after the test was observed with an optical microscope, it was found that the microneedle was bent so as to fall from near the root.

  A skin perforation test was conducted on 10 sheets of the produced sheets (samples 602 to 611) (Table 2). According to 10 skin perforation tests, the average perforation probability was 79.1%.

  Moreover, the deformation | transformation probability of the microneedle (samples 602 to 611) after a piercing | boring test was calculated | required (Table 2). According to ten skin perforation tests, the average deformation probability was 7.2%. As a result of observation, no microneedle damaged by perforation was found. From the above, it has been found that the microneedle shown in FIG. 13 may not be sufficiently rigid for skin perforation.

  FIG. 15A shows H1 / D1 and H2 / D2 of the microneedles used in Examples 1 to 3 and Comparative Examples 1 to 3. A frame 151 in FIG. 15A indicates a range where H1 / D1 is 1.5 or more and 3.0 or less and H2 / D2 is 0.5 or more and less than 1.5. Further, numerals 101 to 601 attached to each point in the figure correspond to the sample numbers of the microneedles used in Examples 1 to 3 and Comparative Examples 1 to 3.

  FIG. 15B shows the buckling load of the microneedle used in Examples 1 to 3 and Comparative Examples 1 to 3. A point 152 shown in white in FIG. 15B indicates that the microneedle did not bend in the buckling test and sunk into the substrate.

  As shown in FIGS. 15A and 15B, from the results of Examples 1 to 3 and Comparative Examples 1 to 3, only the microneedle in the frame 151 has a large rigidity against the load from directly above. It has been found that even in buckling tests, it behaves as if sinking into the substrate without changing its shape.

FIG. 1 schematically illustrates the shape of a microneedle composed of a body portion and a top portion according to the present invention by a cross-sectional view. 2A to 2F schematically illustrate the shape of a microneedle composed of a top portion and a body portion of the present invention. (G) schematically illustrates a microneedle shape different from the microneedle of the present invention. FIG. 3 is a schematic diagram showing the layout of the microneedles used in Examples 1 to 3 and Comparative Examples 1 to 3 on a sheet. FIG. 4A is a schematic view of the microneedle used in Example 1 as viewed from the side, and FIG. 4B is a schematic view of the microneedle used in Example 1 as viewed from above. FIG. 5 is one of the microneedles (sample 101) formed on the sheet used in Example 1, and is a photograph taken with a scanning electron microscope. FIG. 6 is one of the load-displacement diagrams obtained by the buckling test performed in Example 1. FIG. 7A is a schematic view of the microneedles used in Example 2 as viewed from the side, and FIG. 7B is a schematic view of the microneedles used in Example 2 as viewed from above. FIG. 8A is a schematic view of the microneedle used in Example 3 as viewed from the side, and FIG. 8B is a schematic view of the microneedle used in Example 3 as viewed from above. FIG. 9A is a schematic view of the microneedles used in Comparative Example 1 as seen from the side, and FIG. 9B is a schematic view of the microneedles used in Comparative Example 1 as seen from above. FIG. 10 is one of the microneedles (sample 401) formed on the sheet used in Comparative Example 1, and is a photograph taken with a scanning electron microscope. FIG. 11A is a schematic view of the microneedles used in Comparative Example 2 as viewed from the side, and FIG. 11B is a schematic view of the microneedles used in Comparative Example 2 as viewed from above. FIG. 12 is one of the microneedles (sample 501) formed on the sheet used in Comparative Example 2, and is a photograph taken with a scanning electron microscope. FIG. 13A is a schematic view of the microneedles used in Comparative Example 3 as seen from the side, and FIG. 13B is a schematic view of the microneedles used in Comparative Example 3 as seen from above. FIG. 14 is one of the microneedles (sample 601) formed on the sheet used in Comparative Example 3, and is a photograph taken with a scanning electron microscope. FIG. 15A is a diagram showing the relationship between H1 / D1 and H2 / D2 of the microneedles used in Examples 1 to 3 and Comparative Examples 1 to 3, and FIG. ~ 3 and the buckling load of the microneedle used in Comparative Examples 1-3.

Explanation of symbols

DESCRIPTION OF SYMBOLS 11 Top part of microneedle 12 Body part of microneedle 13 Interface surface of body part and top part 14 Taper angle of body part 15 Taper angle of top part 31 Microneedle shape | molded on sheet | seat 41 Interface surface of body part and top part 71 Body part Boundary surface between the top part and 81 Boundary surface between the body part and the top part 91 Boundary surface between the body part and the top part 131 Boundary surface between the trunk part and the top part 151 H1 / D1 is 1.5 or more and 3.0 or less, H2 / D2 is 0.5 Frame showing the portion in the range of less than 1.5. 152 In the buckling test, it shows that the microneedle is not bent and sinks into the substrate as it is.

Claims (13)

  A resin-made microneedle, wherein the ratio H1 / D1 of the height H1 of the body portion of the microneedle to the bottom surface diameter D1 is 1.5 or more and 3.0 or less, and the ratio of the height H2 of the top portion to the bottom surface diameter D2 A microneedle having H2 / D2 of 0.5 or more and less than 1.5.   The microneedle according to claim 1, wherein a ratio D2 / D1 of the bottom surface diameter D2 of the top portion and the bottom surface diameter D1 of the body portion is 0.5 or more and 1.0 or less. The microneedle according to claim 1 or 2, wherein a ratio D3 / D2 of the top surface diameter D3 and the top bottom surface diameter D2 is 0.1 or more and 0.6 or less. The microneedle according to any one of claims 1 to 3, wherein a ratio H1 / H of the height H1 of the body portion and the height H of the macroneedle is 0.5 or more and 0.95 or less.   The microneedle according to any one of claims 1 to 4, wherein a bottom surface diameter D1 of the body portion is 30 to 100 µm.   The macroneedle according to claim 1, wherein the microneedle has a height H of 100 to 300 μm.   The microneedle according to any one of claims 1 to 6, wherein the top surface has a top surface diameter D3 of 1 to 30 µm.   The microneedle according to any one of claims 1 to 7, wherein the body portion has a truncated cone shape.   The microneedle according to any one of claims 1 to 7, wherein the body portion has a polygonal frustum shape.   The microneedle according to any one of claims 1 to 9, wherein the shape of the top is a truncated cone.   The microneedle according to any one of claims 1 to 9, wherein the shape of the top is a polygonal frustum shape.   The microneedle according to claim 1, comprising a thermoplastic resin as a main component.   The microneedle according to claim 1, comprising a polyester resin as a main component.